Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.
Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.
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DOI：
10.4049/jimmunol.1003150
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Baker BM
中科院分区：
文献类型：
--
作者：
Borbulevych OY;Piepenbrink KH;Baker BM
外源抗原和自身抗原之间的分子模拟是T细胞受体交叉反应性的机制，并被认为有助于自身免疫的发展。当由I类MHC HLA-A2呈递时，αβ TCR A6识别来自病毒HTLV-1的外源抗原Tax。在与自身免疫性疾病HAM/TSP的可能联系中，A6还在HLA-A2的背景下识别来自神经元蛋白HuD的自身肽。我们发现HuD和Tax表位与HLA-A2的复合物是接近但不完美的结构模拟物，并且与TCR与自身抗原的其他最近结构相比，A6以与Tax相同的传统结合模式接合HuD抗原。虽然肽和MHC构象变化是HuD识别所需的，但Tax不需要，并且单个羟基的差异触发了TCR环构象的改变，但TCR对HuD的亲和力仍在被认为导致阴性选择的范围内。进一步探索，我们发现HuD/HLA-A2复合物仅是弱稳定的。总的来说，这些发现有助于阐明分子模拟如何驱动自身/非自身交叉反应性，并说明低肽/MHC稳定性如何允许表达自身反应性TCR的T细胞存活，尽管如此，这些TCR仍以传统的结合模式结合。
Molecular mimicry between foreign and self antigens is a mechanism of T cell receptor cross-reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign antigen Tax from the virus HTLV-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease HAM/TSP, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found here that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics, and that in contrast with other recent structures of TCRs with self antigens, A6 engages the HuD antigen with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity towards HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD/HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/non-self cross-reactivity and illustrate how low peptide/MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.
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影响因子：
15.3
作者：
Baker, BM;Turner, RV;Biddison, WE
通讯作者：
Biddison, WE
DOI：
10.1093/protein/gzg087
发表时间：
2003-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Boulter, JM;Glick, M;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
64.5
作者：
Colf, Leremy A.;Bankovich, Alexander J.;Garcia, K. Christopher
通讯作者：
Garcia, K. Christopher
影响因子：
5.6
作者：
Gagnon, Susan J.;Borbulevych, Oleg Y.;Baker, Brian M.
通讯作者：
Baker, Brian M.
影响因子：
4.4
作者：
Borbulevych, OY;Baxter, TK;Baker, BM
通讯作者：
Baker, BM